Abstract Psoriasis is characterized by activation of T cells with a type 1 cytokine profile. IL-12 and IL-23 produced by APCs are essential for inducing Th1 effector cells. Promising clinical results of administration of an Ab specific for the p40 subunit of IL-12 and IL-23 (anti-IL-12p40) have been reported recently. This study evaluated histological changes and mRNA expression of relevant cytokines and chemokines in psoriatic skin lesions following a single administration of anti-IL-12p40, using immunohistochemistry and real-time RT-PCR. Expression levels of type 1 cytokine (IFN-γ) and chemokines (IL-8, IFN-γ-inducible protein-10, and MCP-1) were significantly reduced at 2 wk posttreatment. The rapid decrease of these expression levels preceded clinical response and histologic changes. Interestingly, the level of an anti-inflammatory cytokine, IL-10, was also significantly reduced. Significant reductions in TNF-α levels and infiltrating T cells were observed in high responders (improvement in clinical score, ≥75% at 16 wk), but not in low responders. Of importance, the levels of APC cytokines, IL-12p40 and IL-23p19, were significantly decreased in both responder populations, with larger decreases in high responders. In addition, baseline levels of TNF-α significantly correlated with the clinical improvement at 16 wk, suggesting that these levels may predict therapeutic responsiveness to anti-IL-12p40. Thus, in a human Th1-mediated disease, blockade of APC cytokines by anti-IL-12p40 down-regulates expression of type 1 cytokines and chemokines that are downstream of IL-12/IL-23, and also IL-12/IL-23 themselves, with a pattern indicative of coordinated deactivation of APCs and Th1 cells.
From the flashes of fireflies to Josephson junctions and power infrastructure, networks of coupled phase oscillators provide a powerful framework to describe synchronization phenomena in many natural and engineered systems. Most real-world networks are under the influence of noisy, random inputs, potentially inhibiting synchronization. While noise is unavoidable, here we show that there exist optimal noise patterns which minimize desynchronizing effects and even enhance order. Specifically, using analytical arguments we show that in the case of a two-oscillator model, there exists a sharp transition from a regime where the optimal synchrony-enhancing noise is perfectly anticorrelated, to one where the optimal noise is correlated. More generally, we then use numerical optimization methods to demonstrate that there exist anticorrelated noise patterns that optimally enhance synchronization in large complex oscillator networks. Our results may have implications in networks such as power grids and neuronal networks, which are subject to significant amounts of correlated input noise.
Medication induced esophagitis (MIE) has been reported in dermatology patients taking tetracycline antibiotics. The symptoms of esophagitis, preventable with proper instruction, can create morbidity and lead to increased costs for patients. Our study sought to quantify the incidence of MIE in patients taking tetracycline antibiotics and to investigate how these patients develop MIE. A cross-sectional questionnaire survey was given at outpatient dermatology clinics. Ninety-three surveys from patients who had taken tetracycline antibiotics and 48 surveys from a control group were analyzed. Incidence of esophagitis symptoms (difficulty or pain with swallowing) was measured in both survey and control groups. We found that esophagitis is significantly more common in patients taking tetracycline and its derivatives as compared with a control group (p<.03). Patients should be counseled to take tetracycline antibiotics in an upright position with a large amount of fluid and to report esophagitis symptoms to the prescribing physician.
We report a precise measurement of the isotope shifts in the $4^2$S$_{1/2} \rightarrow 3^2$D$_{3/2}$ electric quadrupole transition at 732~nm in $^{40 - 42,44,48}$Ca$^+$ via high-resolution laser spectroscopy of co-trapped ions, finding measured shifts of 2,775,392,374.8(6.0), 5,347,679,835.1(5.9), and 10,003,129,115.1(5.7)\,Hz between $^{42,44,48}$Ca$^+$and $^{40}$Ca$^+$, respectively. When combined with prior measurements on the $4^2$S$_{1/2} \rightarrow 3^2$D$_{5/2}$ transition [Phys. Rev. A 100, 022514 (2019), https://journals.aps.org/pra/abstract/10.1103/PhysRevA.100.022514] a King Plot analysis shows the data to be consistent with linearity below the level of parts per billion. This observed linearity, which is free of nuclear systematics, improves the previous isotope-shift based limits of Ca$^+$ for couplings of a scalar boson beyond the Standard Model to electrons and neutrons by a factor of 3. Our new limit excludes part of the coupling range remaining for a new physics interpretation after accounting for one higher-order nuclear term in the nonlinear King plot of Yb/Yb$^+$.
In the March 2008 issue of The American Journal of Surgical Pathology, Drs. Fletcher and Gleason discussed the results of the largest review series to date of deep benign fibrous histiocytomas (FHs), a subset of FHs arising within subcutaneous or deep soft tissue.1 Of the 102 cases initially retrieved from consultation files, multiple cases were reclassified as other tumors, including solitary fibrous tumor, primarily dermal cellular fibrous histiocytoma, perineurioma, aneurysmal fibrous histiocytoma, and dermatofibrosarcoma protuberans. Review findings of the remaining 69 cases showed a propensity for the extremities (58% of cases) as compared to the head and neck (22%), trunk (11%), and retroperitoneum, mediastinum, and pelvis (9%). There was a male predominance of 41 males to 28 females with an age range of 6 to 84 years (median age, 37 years). The lesions typically presented as painless masses, present for a wide range of times. The deeper seated lesions of the visceral soft tissues tended to be larger than their subcutaneous counterparts; 9.0 cm as compared to 2.5 cm. Interestingly, 11 cases were reported by the surgeon to be attached to fascia or tendon. The tumors were pseudoencapsulated, well-circumscribed nodules within the subcutis with rare extension into the dermis. In all cases, a storiform pattern composed of plump to ovoid spindle cells with bland nuclei was identified. Lymphocytes were interspersed in all cases and other admixed cell types include foam cells, multinucleate giant cells, and osteoclast-like giant cells (10 cases). The mitotic rate was quite variable, ranging from <1 to 66/10 high power fields. Other features included the presence of tumor necrosis (2 cases), lymphovascular invasion (1 case), and atypical mitoses in conjunction with pleomorphic bizarre nuclei (2 cases) such as that seen within atypical FH. Hemangiopericytoma-like branching vessels were identified in 42% of tumors (29 cases). Stromal hyalinization, myxoid change, hemorrhage, cystic degeneration, and metaplastic ossification were variably present. Immunohistochemically, 40% (20 of 50 cases) were positive for CD34 with 12 cases demonstrating >50% positivity within tumor cells. Of the 15 cases positive for smooth muscle actin (38%), there was less expression within the tumor cells (10 of 15 cases with <50% positivity) than with CD34. Of the 37 patients with available follow-up data, there was a 22% local recurrence rate at a median of 17 months. All cases of recurrence originated from cases in which the tumor was incompletely or marginally excised. A total of three second recurrences occurred. Of these, one patient had extensive distant metastases to bilateral lungs, liver, mediastinum, scalp, and paravertebral soft tissue and died of disseminated disease. A second patient with an initial 9.0 cm subcutaneous lumbar mass (incompletely excised with subsequent re-excision with clear margins) developed retroperitoneal metastases and died of disease. Those cases associated with local recurrence, metastasis, and death were cytologically indistinguishable from their benign counterparts. The two cases of atypical deep FH did not have known recurrence or metastasis. There is little in the literature regarding deep benign fibrous histiocytomas since Fletcher’s original series of 21 cases published in 1990.2 Since that time, classification criteria have changed and most significantly, the recognition of extrapleural solitary fibrous tumors prompted reappraisal of deep FHs. In the current series,1 5 of the 19 original cases of the 1990 study2 were reclassified as solitary fibrous tumors. The diagnostic differential discussed in this paper includes several CD34 positive tumors, thus questioning the usefulness of this immunostain. Solitary fibrous tumors differ in their overall “patternless” pattern and architecture with alternating hyper- and hypocellular zones. This is in contrast to the more uniform storiform cellularity of deep FHs. Dermatofibrosarcoma protuberans is also considered in the differential, distinguished by its uniform bland nuclear features and its infiltrative growth pattern within the subcutis. Perineurioma may similarly be differentiated by its thin nuclei and elongated bipolar cytoplasmic processes. This recent study emphasizes that deep FHs bear a strong similarity in histologic and clinical presentation to their superficial counterparts. Differences include a tendency for deep FHs to be larger, more circumscribed, often show hemangiopericytoma-like vasculature, and have a higher recurrence rate. The recurrence rate however, is similar to superficial (cutaneous) atypical, cellular, and aneurysmal FHs. Gleason BC, Fletcher CDM. Deep “benign” fibrous histiocytoma: clinicopathologic analysis of 69 cases of a rare tumor indicating occasional metastatic potential. Am J Surg Pathol 2008; 32: 354. Fletcher CD. Benign fibrous histiocytoma of subcutaneous and deep soft tissue: a clinicopathologic analysis of 21 cases. Am J Surg Pathol 1990; 14: 801. Until recently, there have been few reported, reliable immunohistochemical markers for atypical fibroxanthoma (AFX). The diagnosis of AFX has usually been made on the basis of a combination of histologic grounds and exclusion with negative immunohistochemical staining. One of the conventional immunostains for AFX has been CD68, a monocyte-macrophage marker. However, CD68 has been reported to be positive for AFX between 0 and 57% of the time and is also detectable in 86% of malignant melanomas.1 Recently, procollagen 1 (PC1) and CD10 have been reported to be reliable immunohistochemical markers for AFX.2, 3 PC1 is a molecule synthesized by fibrocytes and myofibrocytes as a precursor to collagen.2 CD10 is a cell-surface glycoprotein expressed by B-lymphocytes that is frequently expressed in renal cell carcinomas, leukemias, hepatocellular carcinomas, endometrial sarcomas, breast myoepithelial cells, and melanoma, including metastatic melanoma.3, 4 CD10 is also expressed in cutaneous fibrocytes and dendrocytes, making it a potentially useful marker for AFX.5 In the August 2008 issue of The American Journal of Surgical Pathology, Drs. de Feraudy, Mar, and McCalmont retrospectively evaluated CD10 and PC1 expression in retrieval cases of AFXs and dermatofibromas (DFs).6 Three distinct data sets were studied. Group 1 (cases diagnosed between April and May 2001) consisted of 98 consecutive cases of spindle cell neoplasms in which PC1 antibody was used. Of 47 AFXs, PC1 expression was observed in 45 of 47 cases (96%), with a strong reaction in 78% of cases. Of 13 spindle cell squamous cell carcinomas (SCCs), only 2 cases (15%) exhibited weak focal PC1 expression. Of six spindle cell melanomas, none of the cases exhibited PC1 positivity. Group 2 (cases diagnosed in 2004) consisted of using CD10 antibody in a direct comparison of 11 AFXs, 11 DFs, and 7 epithelioid dermatofibromas (EDFs). All cases of AFXs and DFs showed positivity for CD10 while only 1 of 7 cases of EDFs showed positivity for CD10. Group 3 (cases diagnosed between January and November 2005) examined the use of CD10 antibody in 46 cases of spindle cell neoplasms. Of the 38 cases of AFXs, 37 (97%) labeled with CD10 with 34 (92%) of the cases showed strong labeling. The remaining cases were composed of 4 melanomas, 2 DFs, 1 desmoplastic Spitz nevus, and 1 case of nodular fasciitis. CD10 positivity was observed in the 2 cases of DF and in the 1 case of nodular fasciitis. Cutaneous spindle cell malignancies often present a challenge to the pathologist, as they may have overlapping histologic features. Although the most important diagnosis to establish is melanoma, which is usually accomplished through staining with S100 protein antibody, differentiating between spindle cell SCC and AFX is often difficult. This recent report by de Feraudy et al. evaluates the utility of diagnosing AFX through PC1 and CD10 immunostaining.6 However, one of the difficulties in using the CD10 antibody is the non-specific nature of this stain, which stained all cases of DFs and AFX in the study. Although CD10 antibody is not known to stain SCCs, it has been reported to occasionally stain melanomas.4 As it appears that PC1 expression may have a greater specificity than CD10 in the diagnosis of AFX, one may choose to use only the PC1 antibody (given the relative lack of specificity of CD10 and CD68 antibodies) in combination with a typical panel of immunohistochemical stains for cutaneous spindle cell malignancies (S100 protein, cytokeratin, and smooth muscle actin). A limitation of this study is that there is no direct comparison between the PC1, CD10, and CD68 immunostains. The specificity of these immunostains in tumors with AFX-like morphology has not been established. One cannot conclude whether using either immunostain allows for greater precision or confidence in making a diagnosis of AFX. In addition, a large study comparing the methods of immunostaining for diagnostic inclusion versus exclusion may be useful. Although it is preferable to make a diagnosis through positive immunohistochemical staining, currently the exclusion of the two more aggressive entities (SCC and melanoma) with negative immunohistochemical staining remains the method of choice. In the future, the PC1 antibody may be useful in combination with another marker to establish a diagnosis of AFX. A recent paper by Pouryazdanparast et al.7 has shown that CD163 was expressed in 11 of 14 (79%) AFXs with moderate to strong intensity. If its specificity as a marker for AFX is established, a combination of PC1 and CD163 may offer utility in the diagnosis of AFX.
